Type 1 diabetes results from an inadequate amount of functioning beta cell mass caused by T cell-mediated autoimmune destruction. In an NOD mouse model of type 1 diabetes, development of diabetes can be prevented by anti-T cell immunotherapy started early before the appearance of insulitis. However, treatment of diabetes-prone, yet non-diabetic individuals, particularly juveniles, with immunosuppressive drugs is not a desirable form of therapy because of potential complications associated with chronic use of the drugs. In contrast, immunotherapy of patients with full-blown autoimmune diabetes may be well justified if the therapy has the potential to achieve clinical disease remission. We have shown that treatment of overtly diabetic NOD mice with antilymphocyte serum (ALS), a polyclonal anti-T cell antibody, induces long-term clinical remission in approximately 50 percent (or 75 percent if treatment starts within 2 weeks after disease onset) of treated mice and induces autoimmune-free conditions. Our results were subsequently confirmed by Chatenoud et al. who used monoclonal anti-CD3 antibody as an anti-T cell reagent. The overall objective of the proposed study is to design an effective treatment regimen which will effectively induce disease remission in patients with full-blown diabetes. We will investigate two therapeutic approaches using an NOD mouse model of type 1 diabetes. First, we will investigate the effectiveness of combining ALS and exendin-4, an agent which has been shown to promote insulin secretion, beta cell replication and differentiation, in increasing the incidence of disease remission with shorter recovery time. Second, we will investigate whether application of an ALS/rapamycin/donor BMC-infusion protocol, an effective non-radiation-based allograft tolerance induction protocol, can be used to restore long-lasting normoglycemia following islet allotransplantation in overtly diabetic NOD mice. We believe that the results obtained from the proposed study will contribute to the establishment of a clinically applicable therapeutic regimen to treat patients with full-blown diabetes.